Pseudomonas aeruginosa: a pathogen making itself at home
Authors: Helen Stölting, Clare M. Lloyd
Journal: Trends in Immunology (2022)

Upon bacterial infection, mounting the appropriate immune response is paramount to effective pathogen clearance. In a recent study, Agaronyan et al. show how Pseudomonas aeruginosa can divert host immunity to boost type 2 responses and drive mucus production, which can then act as a nutrient source for bacteria. Upon bacterial infection, mounting the appropriate immune response is paramount to effective pathogen clearance. In a recent study, Agaronyan et al. show how Pseudomonas aeruginosa can divert host immunity to boost type 2 responses and drive mucus production, which can then act as a nutrient source for bacteria. Bacterial pathogens and the host immune system are engaged in continual coevolution, with the highly specialized defenses of the immune system exerting pressure on the bacteria to devise ways to evade detection and clearance. Successful immune evasion is critical for bacterial survival, so it is not surprising that many bacteria use sophisticated evasion strategies. These may include biofilm formation and molecular mimicry to avoid detection or direct interference with host effector molecules to subvert the host immune response. A less explored bacterial strategy is the deviation of host immunity towards the wrong type of effector response. The type of immune response mounted by the host is tailored according to the initiating stimulus and can be broadly subdivided into three major classes. Type 1 immune responses, driven by IFN-γ producing lymphocytes such as TH1 CD4+ and CD8+ T cells, type 1 innate lymphoid cells (ILC1), and natural killer cells, as well as mononuclear phagocytes, are particularly effective against intracellular pathogens. In contrast, type 3 responses are tailored to defense against extracellular bacteria and fungi and are characterized by TH17 cells, ILC3, neutrophilia, as well as the production of effector cytokines IL-17 and IL-22. Type 2 responses encompass TH2 cells and ILC2 capable of producing the cytokines IL-4, IL-5, and IL-13, which induce activation of eosinophils, basophils, and mast cells, and drive IgE generation; these have evolved to protect against helminths but also underlie allergic responses towards innocuous antigens in affected individuals [1.Annunziato F. et al.The 3 major types of innate and adaptive cell-mediated effector immunity.J. Allergy Clin. Immunol. 2015; 135: 626-635Abstract Full Text Full Text PDF PubMed Scopus (377) Google Scholar]. In a recent study, Agaronyan et al. [2.Agaronyan K. et al.Tissue remodeling by an opportunistic pathogen triggers allergic inflammation.Immunity. 2022; 55: 895-911Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar] demonstrate that Pseudomonas aeruginosa, a gram-negative, opportunistic, ubiquitous environmental bacterium, can induce and augment type 2 immune responses and exploit host pathways for nutrient generation. By using a human epithelial cell line and mouse lung organ cultures, the authors delineated a mechanism by which P. aeruginosa metalloprotease LasB could cleave the host-derived growth factor amphiregulin (AREG) into a novel, bioactive form, which induced expression of type 2-related genes Areg, thymic stromal lymphopoietin (Tslp), as well as the mucin Muc5ac via binding to the epidermal growth factor receptor (EGFR). When administered in vivo either alone or in conjunction with the innocuous antigen ovalbumin (OVA) in experimental mouse models of allergic skin or airway inflammation, LasB both initiated and augmented classical features of type 2 inflammation, such as eosinophilia, type 2 cytokine (IL-4, IL-5, IL-13) expression, mucus production, and the generation of IgE and IgG1 antibody responses. In addition to experiments using purified LasB toxin, type 2 immune deviation during allergic airway inflammation was also demonstrated using noninfectious doses of the P. aeruginosa strain PA01. P. aeruginosa's adjuvant activity was dependent on the activity of LasB and largely on the expression of AREG by the host, albeit in a somewhat model-dependent manner. Importantly, P. aeruginosa displayed reduced growth in AREG-deficient mice (Areg–/–) demonstrating a key role for this growth factor in successful lung infection and colonization by the pathogen. AREG's importance for P. aeruginosa is further underscored by its ability to induce mucus production, which the authors showed supported bacterial growth, likely by acting as a nutrient source. Overall, this study demonstrated that P. aeruginosa can use its endogenous toxins to exploit host growth factor signaling and specifically augment a type 2 response that is suboptimal for host defense but which enhances mucus, thus providing a supportive local niche to facilitate the bacterium's own growth. While harmless in healthy individuals, P. aeruginosa is an opportunistic pathogen known to cause invasive and life-threatening infections in the immunocompromised. Chronic infection with P. aeruginosa commonly occurs in patients with cystic fibrosis (CF) and is known to be a leading cause of morbidity and mortality. The pathogen's inherent multidrug resistance, superb ability to adapt to the host environment, and expression of various toxins and virulence factors render P. aeruginosa infections challenging to treat and new therapeutic strategies are desperately needed [3.Faure E. et al.Pseudomonas aeruginosa in chronic lung infections: how to adapt within the host?.Front. Immunol. 2018; 9: 2416Crossref PubMed Scopus (77) Google Scholar]. A comprehensive understanding of the molecular mechanisms underlying its pathogenesis is essential for the development of new putative treatments. Agaronyan and colleagues [2.Agaronyan K. et al.Tissue remodeling by an opportunistic pathogen triggers allergic inflammation.Immunity. 2022; 55: 895-911Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar] demonstrated the unique ability of P. aeruginosa to divert the host immune system towards type 2 responses, revealing a relatively unexplored mechanism of bacterial immune evasion with the potential to provide a significant growth advantage to the pathogen. Consistent with this, an earlier study assessing the effect of chronic P. aeruginosa infection on the TH1/TH2 balance in bronchoalveolar lavage of patients with CF found that P. aeruginosa infection was associated with augmented type 2 cytokine concentrations [4.Hartl D. et al.Pulmonary T(H)2 response in Pseudomonas aeruginosa-infected patients with cystic fibrosis.J. Allergy Clin. Immunol. 2006; 117: 204-211Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar]. Of note, a recent study using IL-2 administration to boost TH1 responses during P. aeruginosa infection in mice reported some improvement in macroscopic lung pathology in IL-2-treated animals [5.Calum H.P. et al.Early IL-2 treatment of mice with Pseudomonas aeruginosa pneumonia induced PMN-dominating response and reduced lung pathology.APMIS. 2020; 128: 647-653Crossref PubMed Scopus (1) Google Scholar]; this was intriguing as it suggested that deviation of the host immune response might be a worthwhile treatment approach to test. Accordingly, many novel biologic agents specifically designed to target type 2 immune pathways, such as type 2 cytokines, can reduce exacerbated symptoms in severe asthma patients [6.Wenzel S. et al.Dupilumab in persistent asthma with elevated eosinophil levels.N. Engl. J. Med. 2013; 368: 2455-2466Crossref PubMed Scopus (966) Google Scholar] (Figure 1). To our knowledge, no studies have specifically shown a reduction in airway mucus or in bacterial load, but dual blockade of IL-4 and IL-13 in a mouse allergic airway disease model was associated with reduced goblet cell metaplasia compared with controls [7.Le Floc'h A. et al.Dual blockade of IL-4 and IL-13 with dupilumab, an IL-4Ralpha antibody, is required to broadly inhibit type 2 inflammation.Allergy. 2020; 75: 1188-1204Crossref PubMed Scopus (85) Google Scholar]. This raises the intriguing possibility that using type 2 biologics might represent a novel strategy for treating chronic P. aeruginosa infection by targeting mucus production, thereby limiting bacterial growth. While Medzhitov's group in this study [2.Agaronyan K. et al.Tissue remodeling by an opportunistic pathogen triggers allergic inflammation.Immunity. 2022; 55: 895-911Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar] is the first to describe bacterial immune deviation in detail, the ability to drive type 2 responses has also been reported for other bacteria, such as Staphylococcus aureus [8.Lan F. et al.Staphylococcus aureus induces a mucosal type 2 immune response via epithelial cell-derived cytokines.Am. J. Respir. Crit. Care Med. 2018; 198: 452-463Crossref PubMed Scopus (52) Google Scholar], making it an important aim to investigate whether other bacteria also use immune deviation as part of their survival strategy. This is of particular relevance for pathogens such as Haemophilus influenzae or Moraxella catarrhalis, which are known to cause exacerbations of chronic lung diseases such as chronic obstructive lung disease (COPD). Notably, those lung conditions that predispose to chronic bacterial infections, such as CF and COPD, are often characterized by excess mucus. Indeed, a recent study showed that patients with COPD exhibited higher sputum MUC5AC amounts during exacerbations compared to stable disease and this correlated with airway bacterial load (as a secondary infection) [9.Singanayagam A. et al.Airway mucins promote immunopathology in virus-exacerbated chronic obstructive pulmonary disease.J. Clin. Invest. 2022; 132e120901Crossref PubMed Scopus (1) Google Scholar]. In this study, EGFR inhibition reduced mucus production and inflammation as well as bacterial load in a mouse model of rhinovirus RV-A16-exacerbated COPD [9.Singanayagam A. et al.Airway mucins promote immunopathology in virus-exacerbated chronic obstructive pulmonary disease.J. Clin. Invest. 2022; 132e120901Crossref PubMed Scopus (1) Google Scholar]. Moreover, a randomized, double-blind, placebo-controlled Phase 2 clinical trial of an inhaled EGFR inhibitor (BIBW 2948 BS) showed reduced mucus production in COPD patients, albeit only at high doses (https://clinicaltrials.gov/ct2/show/NCT00423137) [10.Woodruff P.G. et al.Safety and efficacy of an inhaled epidermal growth factor receptor inhibitor (BIBW 2948 BS) in chronic obstructive pulmonary disease.Am. J. Respir. Crit. Care Med. 2010; 181: 438-445Crossref PubMed Scopus (65) Google Scholar]. Thus, a further understanding of the mechanisms that bacteria use to subvert the host immune system, facilitating their growth and survival (including EGFR-associated pathways), is essential to inform the design of novel candidate antibiotic therapies for chronic pulmonary bacterial infections. Furthermore, the use of mucus metabolism by different bacterial species, as well as its importance as a nutrient source during chronic lung infections, certainly warrants further investigation. No interests are declared. CML is supported by a Wellcome Investigator Award (220254/Z/20/Z). HS is supported by a Studentship from the British Lung Foundation. Tissue remodeling by an opportunistic pathogen triggers allergic inflammationAgaronyan et al.ImmunityApril 27, 2022In BriefPathogens manipulate the host immune system to induce the wrong effector response known as immune deviation; however, the mechanisms of immune deviation are poorly understood. Agaronyan et al. demonstrate that Pseudomonas aeruginosa induces host mucin production to promote tissue remodeling and, as a by-product, allergic immune response. Full-Text PDF